eMedicine Specialties > Radiology > Cardiac

Coronary Artery Disease

Author: Justin D Pearlman, MD, PhD, ME, MA, Director of Advanced Cardiovascular Imaging, Professor of Medicine, Professor of Radiology, Adjunct Professor, Thayer Bioengineering and Computer Science, Dartmouth-Hitchcock Medical Center
Contributor Information and Disclosures

Updated: Jun 17, 2009

Introduction

Background

Coronary artery disease (CAD) is a complex disease that causes reduced or absent blood flow in one or more of the arteries that encircle and supply the heart. The disease may be focal or diffuse. Apart from rare congenital anomalies (birth defects), CAD is usually a degenerative disease, uncommon as a clinical problem before the age of 30 years and common by the age of 60 years. One in four people will have a heart attack. The first recognized symptom may be death. The term coronary is derived from crown, referring to the way these arteries sit on the heart.

When the heart has inadequate blood supply (ie, ischemia), pressure may be felt in the chest that moves to the left arm; one may feel weak, sweaty, or short of breath or nauseated; palpitations (ie, change in heart rhythm) may occur; or there may be a sensation of pressure or tightness just in the chest, neck, or arms. Many patients mistake the heart warning symptoms for heartburn or gas. If symptoms occur that may represent inadequate blood supply to the heart one should rest immediately and take nitroglycerin, if available. If symptoms last more than 5 minutes, occur at rest, or keep coming back, one should call 911, chew a full-sized aspirin (325 mg) if not allergic, and continue taking nitroglycerin every 5 minutes as long as it does not cause dizziness or light-headedness.

For excellent patient education resources, see eMedicine's Cholesterol Center. Also, visit eMedicine's patient education articles Chest Pain, Coronary Heart Disease, and Heart Attack.

Severity of CAD

The severity of CAD is defined several ways: (1) anatomically, by visualizing the blood vessel branches and any blockages to blood flow along the pathways; (2) functionally, by estimating blood delivery to tissue supplied by each branch vessel; and (3) clinically, by determining what symptoms correspond to inadequate blood delivery, what level of activity causes them, what relieves them, and the pattern of occurrences. Such patterns are described as unstable if the pattern includes variable or accelerating frequency, variable or increasing severity or changing character of symptoms, or variable or decreasing exercise threshold or if symptoms continue or recur just after a heart attack.

In addition, one examines the consequences, including the location and extent of reversible and of permanent impairment, motion and thickening of affected segments of the heart, and whether the damage is causing or sustaining life-threatening arrhythmias. One also evaluates the patient's overall cardiac performance, which is typically expressed as the ejection fraction (EF), or percentage of the contents the left ventricle pumps forward in a heartbeat, and exertion tolerance, graded 1-4 (1=normal, 4=bedridden).

The TIMI (Thrombolysis in Myocardial Infarction) risk score looks at 7 factors that point to bad outcomes: age 65 years or older, at least 3 risk factors for coronary artery disease, prior coronary stenosis of 50% or more, ST-segment deviation on electrocardiogram at presentation greater than 0.5 mm, at least 2 anginal events in prior 24 hours, use of aspirin in prior 7 days, and elevated serum cardiac markers. TIMI risk scores have the following risk of all-cause mortality, new or recurrent MI, or severe recurrent ischemia requiring urgent revascularization within the first 2 weeks: 1=5%, 2=8%, 3=13%, 4=20%, 5=26%, 6/7=41%.¹

Imaging of CAD

At present, achieving the best resolution on images of the coronary arteries requires catheterization, injection of an iodinated contrast agent, and use of a radiographic technique. As an alternative, multidetector-row CT (MDCT) or MRI may be used to clarify coronary anatomy and to determine whether a vessel is occluded.

Stress imaging has a complementary role in depicting zones with inducible ischemia (blood supply inadequate for the demands of the tissue). Stress may be produced with exercise, an infusion of a medication that increases the strength of cardiac contractions (eg, dobutamine), or an infusion of a medication (eg, adenosine, dipyridamole) that dilates the vessels and thereby reduces the delivery of blood to diseased branches.

More than a decade ago, MRI was shown to be capable of imaging the coronary arteries and demonstrating stenoses without catheterization or injection of contrast material.² More recently, MDCT is proving to be a fast and useful alternative for defining the coronary anatomy.³ MRI takes more time than MDCT and generally provides less detail of the coronary anatomy, but it avoids ionizing radiation and the use of iodinated contrast agent.

Advances in MRI and CT have markedly improved the speed and resolution of imaging, making these modalities useful in the clinical evaluation of CAD while improving their safety and convenience. In addition to defining the anatomy, both MRI and CT can be used to identify zones of impaired blood supply by timing of the arrival of contrast agent–labeled blood.

In addition, MRI is useful in identifying the location and thickness of myocardial scars. Although neither MRI nor CT has replaced x-ray angiography (XRA) as the clinical standard for the diagnosis of coronary stenosis, their use in determining if a vessel is open is increasing. Recently, 64-slice multidetector-row CT angiography (CTA) has shown potential as an alternative to x-ray angiography for the identification of coronary blockages.⁴

Assessment of tissue viability

The amount of impairment or damage caused by stenosis obstructing a coronary artery depends on how much of the myocardium the vessel supplies, the severity of the stenosis and any superimposed spasm, the level of demand in the tissue it supplies, and the condition of the tissue it supplies.

When demand exceeds supply, the tissue becomes ischemic, which means blood supply is insufficient to maintain normal metabolism. Myocardial ischemia may cause chest pain, fatigue, shortness of breath, or another form of reduced exertion tolerance. Ischemia may have no symptoms but may be detected as impaired blood delivery, impaired contractile function (wall motion or wall-thickening abnormality on dynamic cardiac imaging series), or interference with the movement of ions (resulting in depolarization and repolarization abnormalities on EKGs as ST-segment shifts, changes in ST and T waves, and/or rhythm abnormalities); and/or it may be detected when a blood test shows a release of enzymes (creatine kinase-MB [CK-MB], troponin-I, troponin-T) from the heart muscle.

Ischemia may deplete high-energy phosphate carriers (eg, creatine, adenosine) that are needed for muscle contraction. Depletion may occur to the point that impaired motion may persist even when ischemia is relieved. Transiently impaired contractile function of muscle that persists after the relief from ischemia is called stun, and long-term dysfunction of viable muscle is called hibernation.

Dead tissue converted to scar likewise loses contractile function. Therefore, a key issue when a region of heart wall shows loss of function is the determination of whether the myocardium is still viable. Persistent wall-motion abnormality at rest shown by imaging (echocardiography, MRI, CT, x-ray angiography) can raise the issue of tissue viability and, in particular, whether repairing a blockage in the blood supply is likely to be beneficial.

If a region is thin and akinetic (no motion), it is more likely to scar (dead myocardium) than if it is not. However, when in doubt, viability tests are appropriate. For example, viability can be identified by performing phosphorus-31 MRI and by reporting for each region the relative concentrations of creatine phosphate; inorganic phosphate; and adenosine monophosphate, diphosphate, and triphosphate.

Although MRI of phosphorylated metabolites and positron emission tomography (PET) of metabolic activity (to assess glucose utilization) can be used to assess tissue viability, an alternative method of equal, if not better, clinical value is imaging by MRI with contrast to identify contrast retention by damaged myocardium. We first observed that phenomenon over a decade ago when studying an animal model of ischemia and infarction while looking at angiogenesis (treatments to promote development of the blood supply).

Another way to identify viability is to examine wall motion at rest and with light stress. Dobutamine stress imaging may be performed with MRI or echocardiography. Dobutamine stress tests are used to detect viability by demonstrating dose-related increases in contractility if the tissue is viable. An increase in the dose of dobutamine may subsequently elicit a decline in contractility associated with induced ischemia — that is, a biphasic response, indicating viable but threatened myocardium.

Early in the development of perfusion imaging^5,6 , we observed retention of gadolinium contrast by injured myocardium. Normally, a bolus of contrast agent washes out of the heart walls within 5-10 minutes. Any contrast agent seen in the heart after the agent has washed out of normal zones demarcates injured myocardium. This technique has since been called MRI scar mapping or delayed enhancement imaging. The fraction of wall thickness that retains gadolinium-based contrast agent 10-20 minutes after a bolus infusion of 20 mL/75 kg indicates viability. The result is an excellent predictor of potential for functional recovery. If the scar is less than one third the thickness of the wall, improvement with revascularization is likely. However, if the scar is more than two thirds the thickness of the wall, improvement after revascularization is unlikely.

MRI scar maps depict contrast retention due to cell disruption. Although acute injury results in slightly enlarged zones of retained contrast agent on MRI, after a week, the defined zone appears the same months to years later and it corresponds on pathology to dead tissue.

Unfortunately, in patients with poor renal function, gadolinium contrast may stay in the body long enough to cause a potentially disabling inflammatory reaction called nephrogenic systemic sclerosis, also known as nephrogenic fibrosing dermopathy (NSF/NFD). That condition has been linked to all the gadolinium-based contrast agents (gadopentetate dimeglumine [Magnevist], gadobenate dimeglumine [MultiHance], gadodiamide [Omniscan], gadoversetamide [OptiMARK], gadoteridol [ProHance]). For more information, see the eMedicine topic Nephrogenic Fibrosing Dermopathy. The disease has occurred in patients with moderate to end-stage renal disease after being given a gadolinium-based contrast agent to enhance MRI or MRA scans.

NSF/NFD is a debilitating and sometimes fatal disease. Characteristics include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes; joint stiffness with trouble moving or straightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness. For more information, see the FDA Public Health Advisory or Medscape. Patients with poor renal function undergoing dialysis have been imaged with coordinated extra dialysis runs to clear the agent.

Pathophysiology

Injury and inflammation

In coronary artery disease (CAD), injury to the endothelial lining of arteries, active uptake by the vascular wall of cholesterol esters, inflammatory reaction, thrombosis, calcification, and hemorrhage all contribute to arteriosclerosis or hardening of an artery wall. Levels of the acute-phase reactant inflammation markers, C-reactive protein and serum amyloid-A protein, are elevated in patients with unstable angina and infarction. Inflammatory cells, including abnormal T-lymphocytes, are seen during autopsy in patients with coronary disease or inflammatory diseases. Patients undergoing a heart attack have elevated white blood counts. Statin medications, which have anti-inflammatory activity, reduce the risk of death from heart attack even when given acutely, without time for the benefit from lowering LDL (low-density lipoprotein cholesterol). Thus, inflammation plays a major role in CAD and heart attacks.^7,8

Whether inflammation causes and promotes the disease or whether it is merely a consequence and marker for a poor prognosis is not entirely clear. In a study of 121,700 women, those with rheumatoid arthritis had twice as many heart attacks as did women without inflammatory disease.⁹ Inflammation has also been implicated in elevating the risk of coronary disease in association with metabolic syndrome (obesity, hypertension, insulin resistance, and dyslipidemia). Hostility (presumably because of changes in hormone levels) is also a risk factor.¹⁰ Patients older than 65 years with antibodies to herpes simplex virus have increased risk of heart attack. The CD3+ lymphocytes, inflammatory cells that accumulate in atherosclerotic plaque, often have DNA to the bacteria Chlamydia pneumoniae, suggesting infection may also contribute to CAD.

Platelets and lipoproteins

In a study of patients with a heart attack who underwent coronary angiography within the previous year, one half of the culprit lesions were narrowed less than 70%; and with non-Q wave MI, less than half had a definite culprit stenosis. Other studies have had differing results, but it is clear that a lesion causing mild stenosis may rupture suddenly and cause bleeding into the wall of the vessel (plaque hemorrhage), promoting occlusion of the vessel because of thrombosis. The final step explains why antiplatelet medications, such as aspirin, can help in preventing heart attack. Thrombotic occlusion of the vessel occurs when platelets stick together to form an obstructive plug; therefore, the inhibition of platelet adhesion by aspirin can prevent thrombosis.

Cholesterol-lowering medications work by reducing or reversing the lipid deposition into the arterial wall in areas of flow stress, and many also have anti-inflammatory effects. Lipid levels can be improved by decreasing the amount of circulating low-density lipoprotein cholesterol (LDL-C) by changing the person's diet, by inhibiting the production of LDL-C in the liver, and/or by decreasing the absorption of LDL-C in the intestines. Furthermore, the rate of uptake of LDL-C into the vessel wall is sensitive to oxidation status, because oxidized LDL-C has a 50-fold increased rate of uptake.

Antioxidants have been suggested as a means to slow the process. In the Women's Health Initiative, patients who took vitamin C supplements had nearly one third fewer heart attacks than those who did not (relative risk of 0.72 and 95% confidence interval of 0.61-0.86 after adjustments were made for age, smoking, and other risk factors).¹¹ Consuming omega-3 fatty acids and drinking a glass of grape juice or red wine a day may help avert heart attacks by similar means. However, trials with vitamin E as an antioxidant have not lowered risk. 

High-density lipoprotein cholesterol (HDL-C) transports lipids from the body back to the liver. Exercise that keeps a heart rate above 130 bpm for at least 10 minutes every other day increases HDL-C levels. Niacin at 2000-3000 mg per day also helps elevate HDL-C values, as well as improve another risk factor, lipoprotein(a). Many patients experience a hot flash or flushed feeling with supplemental niacin, which is often reduced by taking it with 2 glasses of water, with dinner, or a half-hour after taking 325 mg of aspirin. No-flush niacin may not release enough niacin to be effective.

A new class of medication, cholesteryl ester transfer protein (CETP) inhibitors (eg, torcetrapib), was specifically designed to elevate HDL-C concentrations.¹² It was removed from the market after study in combination with atorvastatin showed increased mortality. Each study arm (atorvastatin alone vs torcetrapib + atorvastatin ) had 7500 patients enrolled; the arm receiving atorvastatin alone had 51 deaths, while the torcetrapib + atorvastatin arm had 82 deaths.

Calcification

Chronic lesions may become calcified and therefore provide evidence of the disease process, as seen on CT or electron-beam tomography (EBT). However, the calcification does not necessarily indicate the lesions that pose the greatest risk. In fact, calcified lesions may be more stable than noncalcified ones. However, evidence also suggests that a soft plaque has an increased capacity to remodel outward; therefore, calcification of a vessel is a significant risk factor. Once the degree of narrowing exceeds 50%, stable narrowing of an artery typically results in exercise limitations, which is often experienced as a squeezing chest tightness that may radiate to the jaw or left arm. This tightness (Heberden angina ) is predictable at a specific level of activity.

Angina Pectoris

Angina pectoris (constrictive discomfort in the chest) represents the classic symptoms of CAD.
Many patients do not have classic symptoms. CAD symptoms in patients who have no tightness or pressure in the chest are described as "angina equivalents."

Heberden described tightness in the chest predictable with exertion as a symptom of a dangerous disease that he classified as spasmodic:

"But there is a disorder of the breast marked with strong and peculiar symptoms, considerable for the kind of danger belonging to it, and not extremely rare, which deserves to be mentioned more at length. The seat of it, and sense of strangling, and anxiety with which it is attended, may make it not improperly be called angina pectoris. They who are afflicted with it, are seized while they are walking, (more especially if it be up hill, and soon after eating) with a painful and most disagreeable sensation in the breast, which seems as if it would extinguish life, if it were to increase or continue; but the moment they stand still, all this uneasiness vanishes. "¹³

Patients with diabetes or those who are older than 60 years commonly have no chest pain during ischemia but instead have impaired wall function, which may result in shortness of breath or changes in rhythm that may remain unnoticed or may cause palpitations or syncope. Therefore, stress imaging may help in identifying exercise-inducible ischemia with no symptoms.

Angina lasting more than 10 minutes may actuate a heart attack (by producing ischemia sufficient to cause permanent damage, whereby scar replaces the heart muscle). The mechanism of permanent injury is called apoptosis (cell suicide). Teleologically, it is better to build scar tissue and remove the injured muscle than to have just injured muscle incapable of self-repair that may cause a rupture of the heart wall.

A threatened heart attack is an emergency because it is life threatening and because remaining threat of injury may be reversible with prompt appropriate intervention. The diagnosis should be achieved as quickly as possible. At the early stages, simply chewing an aspirin tablet and/or taking nitroglycerin can often stop the immediate threat.

Appropriate and timely treatment

When symptoms suggestive of a possible threatened heart attack are present (persisting chest pain or pressure radiating to 1 or both arms or jaw; or unexplained shortness of breath, weakness, sudden sweating, or a serious arrhythmia), an electrocardiogram should be obtained promptly, with continual monitoring for arrhythmia or ischemia (impaired blood supply).

Ambulances have both EKG and rhythm and oxygenation monitoring equipment, as do emergency departments. The EKG can show ST segment shifts and/or T-wave inversions as signs of heart ischemia or injury. However, there are electrically silent areas in the standard monitors. A 12-lead EKG does not detect all of the electrical warning signs of heart damage; more extensive thoracic coverage is desirable.

Emergency care offers additional medications that can stop a threatened heart attack (eg, intravenous nitrates, beta-blockers, thrombolytics, anticoagulants), as well as quick transport of the patient to the catheterization laboratory for definitive diagnosis and treatment. Experienced cardiac catheterization laboratories are prepared to repair coronary arteries typically within an hour at any time of the day or night on an emergency basis. One hour has been described as equipoise, or a crossover point; if it will take longer than an hour to get coronary intervention by catheter, then lytics are favored. Contraindications to lytics (clot-busting medication) include the following:

• Prior intracranial hemorrhage
• Cerebral AV malformation 
• Cerebral neoplasm
• Ischemic stroke within 3 months
• Closed head trauma/subdural hematoma within 3 months
• Recent spinal surgery
• Uncontrolled severe hypertension

There is some evidence that in cases of acute ST-elevation MI, if there is a moderate likelihood that it will take longer than an hour to get a catheter intervention, half-dose lytics should be provided, followed promptly by percutaneous catheter intervention (PCI). That strategy is called facilitated PCI. However, the FINESSE¹⁴ and ASSENT¹⁵ clinical trials have argued against that approach. In those studies, patients who went directly to catheterization without half-dose lytic plus abciximab, or abciximab alone, did as well or better even if time to PCI was 1-4 hours. If a regimen is developed with a much lower incidence of bleeding complications (particularly intracranial hemorrhage), facilitated PCI may regain support. If symptoms were prominent and then stopped, that suggests the damage has been curtailed.

If threatened heart attack goes untreated, the tissue that depends on the interrupted blood supply eventually dies, and progressive amounts of irreversible damage accrue. The damaged area is typically small even after occlusion if it is effectively treated within an hour. Delay of more than an hour after occlusion is sufficient to produce life-threatening permanent damage to the heart wall, yet some benefit can still be obtained after 6 hours, or longer, if the damage is incomplete at that time.

Even if revascularization does not prevent damage, it may improve repair in terms of the strength of the scar and the quality of heart remodeling to compensate for the damage (open-artery hypothesis). The duration of chest pain, the timing and pattern of EKG changes, and the timing and area under the curve of enzyme elevation are clues to duration of ongoing damage.

Frequency

United States

Coronary artery disease (CAD) accounts for more than 650,000 deaths per year in the United States, including more than 25% of deaths in persons older than 35 years. Each year, 1.25 million acute myocardial infarctions (MIs) occur. Of these, more than one half occur without previously recognized symptoms. Cardiovascular disease is responsible for more than 3 times as many deaths as all forms of cancer combined. In the United States, spending on CAD exceeds $80 billion per year. One third of people who have a heart attack and who do not receive immediate medical attention die.

International

Coronary artery disease (CAD) is the leading cause of death in developed countries. The incidence is rising in Central Europe and in Eastern Europe, but it is low in Japan. Epidemiologic studies of differences among countries and regions revealed dietary and environmental factors that contribute to disease (eg, saturated fat, cholesterol, abdominal obesity, smoking, exposure to second-hand smoke) and also factors that protect against it (eg, fish oils, vitamin C and other antioxidants, red wine or grape juice, anti-inflammatory agents).

Mortality/Morbidity

In one half of the population, the first recognized symptom of CAD is MI, which is fatal in nearly one half of patients. Taking aspirin at the onset of a heart attack reduces mortality rates.

For individuals who arrive awake at a hospital, short-term survival is good, but long-term survival depends on the anatomy of the coronary arteries and on treatment. Survival after a heart attack has been continually improving over the last 30 years, but the incidence of new heart attacks has recently stabilized.

With the obstruction of 3 vessels, the left main coronary artery, or the equivalent combination of proximal anterior descending and circumflex disease plus reduced heart function (abnormal ejection fraction [EF]), bypass surgery may provide a survival benefit. However, similarly good results may be achievable with drug-eluting stents and complete revascularization by percutaneous intervention (PCI, catheterization).

With 1- or 2-vessel disease that is not equivalent to involvement of the left main coronary artery, medical treatment and catheter interventions are equally good, except in patients with diabetes, in whom surgery has provided the best long-term results. At some centers, catheter intervention may be used to manage 3-vessel disease (eg, with normal function). However, when catheter intervention is used in an acutely ill patient, the focus is on the culprit lesion, and repair of other blockages is deferred.

Morbidity depends on the patient's exercise tolerance and on the amount of damage, which is commonly assessed by using the EF. An EF below 40% typically limits a person's activity, an EF below 30% results in severe limitations plus significantly increases the risk of deadly arrhythmias, and an EF below 20% causes problems at rest.

In patients in whom damage is severe enough to cause clinically significant congestive heart failure, one half die within 5 years. The outlook is improving with rapid access to healthcare and with advancements in treatment. As shown in experimental studies, injected muscle precursor cells may be able to repair dead regions.¹⁶ In clinical studies, implantation of an automated defibrillator prolonged life, reducing the post-MI mortality rate by 31% in patients with persistently low EF.¹⁷

Race

Mortality rates in men do not differ by race, but African-American women have the highest risk of death from heart disease, and their rate of heart attacks is increasing. Native Americans, particularly those living in North Dakota and South Dakota, also have a higher risk for heart disease than do whites. Hispanics have the lowest risk for heart disease compared with all these groups.

African Americans have particular biologic and social risks, including the following:

• High prevalence of diabetes and hypertension
• Poor diet
• High stress levels
• Poor access to health care
• Possible genetic trait that increases the danger of triglycerides, especially in women
• Possibly decreased production of nitric oxide (which is critical for increasing blood flow) in response to stress

To study the effect of discrimination, actors portrayed patients presenting with symptoms of heart disease in 1 study.¹⁸ African-American women were 60% less likely to receive aggressive (and expensive) diagnostic tests than African-American men or whites. More recently, referral rates for intervention were similar for white or black individuals, but African-American patients accepted surgery less often than white patients.¹⁹

African Americans account for 13% of the United States population but only 2-9% of control subjects in most major research trials. Therefore, major studies have been focused more on the treatment of white patients than on black patients, and knowledge of what is best for patients of other races is limited.

Sex

In individuals younger than 65 years who do not smoke and who avoid second-hand smoke, CAD is primarily a disease of men. The difference is attributed to the protective effects of estrogen. Risk factors for significant coronary obstructions that affect both men and women are smoking; exposure to second-hand smoke; diabetes; poor diet; elevated levels of homocysteine, LDL-C, or triglycerides; low HDL-C levels; hypertension; use of birth control pills; and a sedentary lifestyle.

Because more research has been completed in men than in women, less is known about the reliability of screening women. In addition, vascular tone or spasm may play a larger role in women than in men. Therefore, many recommend a decreased threshold for imaging of the coronary arteries in any woman who complains of chest pain, without a consideration of whether the pain is predictable at a particular level of exercise.

Case-fatality rates are higher in women than men. Noninvasive testing in women has been controversial because of a perception of diminished accuracy, limited female representation, and technical limitations (eg, breast artifact). Exercise treadmill testing has an improved accuracy when multiple risk parameters (eg, ST deviation, chest pain, exercise time) are included in the interpretation. For women, a low-risk Duke treadmill score is predictive of a 5-year survival rate of 97%, and fewer than 20% of patients have obstructive disease.

Calcium scoring in women has a sensitivity of 88% and specificity of 49%; values for exercise echocardiography are 86% and 79%, respectively. A quantitative evaluation of perfusion may improve the precision of risk assessment.

Age

• Fatty streaks in vascular walls are observed in people of all ages, even infants. Children may have cardiac ischemia as a result of a stenotic or acutely angled origin of a vessel or another anomaly, such as a vessel pinched between the aorta and pulmonary artery or trapped under a myocardial bridge.
• In an autopsy series of 19-year-old soldiers, coronary lesions were prevalent but amounted to only mild stenosis.
• After the age of 35 years, clinically significant coronary artery disease (CAD) is prevalent in men. Serious disease at that age typically results from cocaine use; smoking or exposure to second-hand smoke; diabetes; or other predisposing factors, such as low HDL, high LDL, beta-subtype of LDL (determined by LDL fractionation), lipoprotein(a), C-reactive protein (CRP), or homocysteine. The lifetime incidence of CAD after the age of 35 years exceeds 1 in 4 people. Autopsy series revealed that 25% of men younger than 25 years and 75% of men older than 25 years have a clinically significant coronary lesion. One in every 4 adults has clinically significant atherosclerotic disease.

Anatomy

Coronary artery disease (CAD) may affect a large coronary artery near the vessel origin at the aortic root (proximal segment) or a small branch vessel far from its origin (distal segment). CAD may affect all 3 of the major supply arteries to the heart: the left anterior descending (LAD) artery, the left circumflex artery (LCX), and the right coronary artery (RCA). Therefore, a simple ranking of disease severity is 1-, 2-, or 3-vessel disease. For this purpose, disease is defined as the presence of 1 or more areas of narrowing of a vessel or major branch by 50% or more from its expected normal diameter (eg, compared with a nearby proximal normal segment without intervening branches). Therefore, 50% narrowing in the LAD, LCX, and RCA is considered 3-vessel disease comparisons of surgery, medical therapy, and catheter interventions.

A 50% reduction in vascular diameter is a reasonable definition of a clinically significant lesion because lesions with 50% or greater stenosis are commonly responsible for heart attacks. The definition is imperfect in that an unstable lesion with only 30% stenosis can also cause a heart attack, and lesions that cause angina are typically stenoses of 70% or greater. It is also imperfect in that stenosis based on diameter does not account for the length of the lesion or its entrance and exit effects (funnel versus abrupt), all of which affect flow reduction. Therefore, clinical judgment is also need in assessing the clinical significance of a lesion, such as whether it supplies a territory with demonstrated jeopardy on stress testing or perfusion assessment. In addition, a Doppler flow wire or intravascular ultrasonography (IVUS) may be applied and/or flow reserve may be estimated to assess the hemodynamic significance of a coronary lesion.

In most people, the LAD and LCX have a common origin from the left coronary sinus of the aortic root, a short vessel called the left main coronary artery. A third of the population has a third artery between these 2 called the ramus intermedius. In uncommon cases, the LAD and LCX have separate origins, both of which arise from the left coronary sinus; or in rare cases (1 in 1000 people), the LCX may originate in another sinus.

In as many as 20% of individuals, the origins are higher than usual, at the junction with the tubular portion of the aorta (sinotubular junction, or STJ). The RCA has a separate origin in the right coronary sinus, but sometimes its origin is at the sinotubular junction (9%) or higher (1%). The aortic cusps corresponding to the coronary arteries normally are anterior and face the pulmonary valve. The third cusp (posterior cusp), just above the aortic valve, typically has no arterial branch, but in a quarter of the population, it gives rise to the right conus artery, a small vessel that is usually the highest branch of the right coronary artery. Anatomic variants are common.

The branches of the LAD are called diagonals and are successively labeled D1, D2, etc. The portion from the left main coronary artery to the first diagonal is called the proximal segment of the LAD. The portion between D1 and D2 is the middle segment, and that beyond D2 is called the distal segment. The distal segment typically covers the anterior aspect of the apex of the left ventricle (LV). However, in 12% of the population, it wraps around to cover the inferior surface of the apex as well (wrap-around LAD). In addition to diagonal branches, the LAD gives off numerous, small septal perforators that supply the anterior two thirds of the intraventricular septum.

The branches of the LCX are called obtuse marginal branches and numbered sequentially (OM1, OM2, etc). The LCX often courses around the base of the heart near the atrioventricular (AV) groove. In 20% of patients, the LCX reaches the crux, where the AV groove meets the posterior interventricular septum and turns to supply the inferior surface of the heart as the posterior descending artery, also known as the posterior interventricular artery. In 85% of people, this artery is a distal continuation of the RCA. If the posterior descending artery stems from the RCA, the circulation is described as right dominant, and if it comes from the LCX, the supply system is called left dominant. In about 5% of patients, both the RCA and the LCX contribute to the PDA (posterior descending artery) territory, a condition described as codominance. The dominant artery delivers blood to the posterior one third of the septum and the AV node, which penetrates the center of the heart from the crux.

The proximal RCA usually (in 60% of the population) supplies the sinoatrial node via a branch that runs between the aortic root and the superior vena cava. In a third of the population, the sinoatrial node comes from the left, and in some individuals, it is supplied form both the right and the left. The RCA courses near the AV groove, extending inferiorly to the right toward the crux (the intersection of the AV groove and the interventricular node). The RCA gives off a large branch called the acute marginal branch before it reaches the crux. The RCA may continue in the AV groove past the crux with LV extension branches, or it may terminate short of the crux. The proximal RCA branches typically include the left atrial artery, the conus artery, the sinoatrial node artery (in 55% of the population), the right atrial artery, and the right or acute marginal artery.

Presentation

Risk factors for coronary artery disease (CAD) are classified as modifiable or unmodifiable.

Modifiable risk factors include smoking, exposure to second-hand smoke, hypertension, high levels of low density cholesterol (LDL-C) levels, low levels of high density cholesterol (HDL-C) levels, high triglyceride levels, high levels of lipoprotein(a), diabetes, abdominal obesity, sedentary lifestyle, avoidance or sudden challenges or stresses, snow shoveling, inadequate beta-blockade, high homocysteine levels, high levels of C-reactive protein (which indicates inflammation), and poor recognition of symptoms and the need to relieve them promptly and fully. HDL should be high (>40 mg/dL or >1 mMol/L in men, >50 or 1.25 in women) and LDL should be low (recommended target ranging from <160 in patients with low risk to <70 in patients with CAD).

Although some physicians are guided by the ratio of HDL to LDL, these function as independent factors that can be optimized separately. LDL is typically lowered by statins, and HDL raised by exercise and niacin. Although high homocysteine is a marker for elevated risk of atherosclerosis and CAD and it is modifiable (lowered by B-12 and folate), trials of treatment have not shown that lowering the homocysteine level reduces the risk of CAD. For patients with a triglyceride concentration of less than 400 mg/dL (<4.5 mmol/L), the LDL-C value can be estimated from a fasting sample of total cholesterol, HDL, and triglycerides by using the following equation:

LDL-C concentration = Total cholesterol concentration - HDL-C concentration - (triglyceride concenration/5).

Alternatively, LDL can be measured directly (D-LDL) without requiring fasting.

Treatment before evidence of disease appears is called primary prevention; treatment afterward is called secondary prevention.

Target levels for LDL-C have been lowered from 160 mg/dL to <100 mg/dL, depending on overall risk, down to a target of <70 mg/dL for patients with known CAD, because the lower levels have proved to help reduce recurrence of heart attack²⁰ .

Cholesterol synthetase inhibitors confer a benefit even in patients with normal LDL-C levels, possibly because of an anti-inflammatory effect. Skin flushing may limit the use of niacin; effects may be lessened if niacin is taken with 2 glasses of water, with dinner, or half an hour after aspirin or if slow-release preparations are used. However, no-flush versions of niacin may not work because it may not release enough niacin to be effective.

Unmodifiable risk factors include age, male sex, and family history. Aggressive lowering of cholesterol levels has reduced individual morbidity and mortality rates in some groups but not the cardiovascular death rate for the overall population.

CAD should be suspected in a patient with any symptoms that may represent cardiac ischemia, such as an ache, pressure, pain, other discomfort, or possibly just decreased activity tolerance due to fatigue, shortness of breath, or palpitations. Discomfort or pressure is especially suggestive when it occurs in the chest, left arm, jaw, or upper abdomen, particularly if it is triggered by exertion, exposure to cold, or shaving and if it is relieved by rest or nitrates. The feeling of discomfort or pressure often radiates from 1 location to another, such as from behind the sternum and down the left arm. Nausea, diaphoresis, and a duration longer than 10 minutes suggest that the episode is turning into a heart attack (cell death).

Cardiac ischemia without chest pain represents a defective warning system regarding angina; this presentation is not uncommon in people older than 60 years or in those with diabetes. Patients may have only decreased exertion tolerance, dyspnea, or palpitations triggered by exertion. Although a timely EKG may show silent ischemia, some areas of the heart are electrically silent, which means that they are not represented on the standard 12-lead EKG (more complete thoracic coverage has been shown to be superior).

Perfusion or wall-motion imaging can help in identifying the problem. Such patients can establish a regular exercise program, such as going easy on even dates and performing a 10-minute reproducible challenge on odd dates, to serve both as a minimal prescription for cardiovascular fitness and as a screening exercise challenge for painless inducible ischemia (a daily regimen and alternating with a light, no-target workload improves compliance for many patients, and an every-other-day cardiovascular challenge suffices for cardiovascular fitness). If the level of challenge is limited by dyspnea (shortness of breath) and fatigue, the patient should notify the physician for consideration of a formal stress test with imaging or evaluation for other possible causes of decreased exertion tolerance, such as salt overload or pulmonary disease.²¹

Preferred Examination

The patient's clinical history (age, symptoms, risk factors) provides an estimate of disease likelihood. The basic screening test is stress EKG, which can adjust prognosis depending on the pretest likelihood of disease. Generally, if the patient has no symptoms and the resting and stress EKGs are normal, the risk of mortality in the next year is low. However, the predictive accuracy of EKG even at peak stress as part of stress testing overall is not good, with as much as one half of all cases of disease missed by EKG. The simple addition of stress testing of B-type natriuretic peptide (BNP) levels in the blood markedly improves the predictive accuracy.²² Other ways to improve accuracy are nuclear imaging, echocardiography, MRI, or CT.

Stress nuclear imaging is widely used to assess the patient's exercise tolerance and to identify zones of inducible ischemia (jeopardized myocardium), which is useful information, even after x-ray angiography is performed. PET offers similar rest-stress data and is superior for identifying viable myocardium. Jeopardy and viability are important issues, because if the myocardium is not at risk or if it is not viable, revascularization (bypass or angioplasty) will not help that part of the heart.

Echocardiography to identify wall motion abnormalities has a similar predictive accuracy in patients with intermediate suspicion of CAD, estimated at 80-90%. Echocardiography avoids radiation exposure, which may cause as much as 1 new cancer for every thousand patients studied, but radionuclide imaging (thallium, sestamibi) is preferred if the patient already has old wall motion abnormalities or has poor echo windows (lung blocks the views). Exercise stress echo may be performed before and after treadmill exercise or during exercise on a supine bicycle. The latter requires more cooperation but allows imaging at every stage, so it may avoid false negatives from rapid recovery or from involvement of all areas (balanced ischemia).

MRI and CT have markedly improved the ability to depict zones of impaired blood supply and to display the coronary anatomy. MRI and CT do not require stress; they offer sensitivity and specificity similar to those of nuclear imaging; they achieve resolution better than that of nuclear imaging; and they can demonstrate the 3-dimensional (3D) coronary anatomy.²³ Therefore, MRI and CT complement the combination of stress test and catheterization, and in some settings, MRI and/or CT may replace them (eg, by demonstrating normal results).

EBT offers similar value. EBT is a form of CT in which an electron beam, rather than the entire x-ray source, is rotated around the patient. Also, EBT and CT have been used as a screening test to screen for calcifications in the coronary arteries as a marker for risk of coronary disease in young patients.

To monitor angiogenesis, collateral-sensitive and delayed-arrival MRI appear to be far more sensitive than any other technique. Collateral-sensitive MRI generates a dark flare of susceptibility effect due to sparse neovascular development at an early stage while suppressing a similar effect from the LV. This finding is a strong predictor (r = 0.93) of improved blood delivery.

Data from quantitative studies of the extent of delayed arrival in humans and from double-blind postmortem evaluations in porcine models of chronic myocardial ischemia and angiogenesis have validated this method.⁵ This finding clearly distinguishes angiogenic treatment from control at 4 weeks after treatment, and the benefit is followed by improvements in wall motion (serial motion assessment by reference tracking [SMART] measurements).²⁴

Limitations of Techniques

X-ray angiography is considered the criterion standard for evaluating coronary artery stenosis. Flow limitations may be estimated by using the TIMI (Thrombolysis in Myocardial Infarction)score and confirmed by using a flow wire or by performing IVUS.²⁵ If x-ray angiography fails to depict a culprit lesion and if cardiac ischemia is inducible, the patient may have syndrome X (microvascular disease).

X-ray angiography requires the use of iodine, which may cause serious allergic reactions, including anaphylaxis and also renal failure. Use of large volumes of saline and the antioxidant acetylcysteine may help prevent renal failure. The catheterization procedure can induce vessel spasm and/or tear the lining of a vessel, resulting in occlusion and, possibly, death in a patient who may not have had coronary artery disease (CAD). The procedure can also result in embolism, which may cause stroke or limb loss. Nerve damage, infection, and other complications are possible as well. The death rate is approximately 0.1%.

Nuclear imaging produces low-resolution images that may depict an apparent defect resulting from breast tissue, hiccups, paradoxical septal motion, or other confounding factors. Nuclear imaging may fail to depict disease because of submaximal stress. Tomographic imaging, attenuation correction, or PET substantively eliminate the problems resulting from breast attenuation. The newer combinations of nuclear imaging with CT enable the most accurate correction of nuclear event maps for attenuation by overlying tissues.

MRI requires special precautions in patients with pacemakers or recently placed aneurysm clip. Patients with claustrophobia require premedication, mirrors, and/or an open magnet. Many magnets do not accommodate patients who weigh more than 300 lb. Arrhythmias commonly lower image quality.

CT contrast agents usually contain iodine, which may cause an allergic reaction and possibly anaphylaxis. Nonionic contrast material reduces the risk of harm, as does pretreatment with steroids. Gadopentetate dimeglumine, the contrast agent used for MRI, may be used for CT if patients are allergic to iodine-based media. CT uses X-rays typically equivalent to the dose needed for about 200 chest radiographs. A single routine CT study in a child increases the lifetime risk of cancer by 0.35% per scan.²⁶ In adults, the lifetime risk of cancer may be as high as 2% with annual CT screening.

Differential Diagnoses

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• Myocardial Ischemia - Nuclear Medicine and Risk Stratification (Radiology)
• Complications of Myocardial Infarction (Cardiology)
• Cardiac Calcifications (Radiology)
• Coronary Artery Atherosclerosis (Cardiology)

• Cholesterol Center
• Coronary Heart Disease Causes
• Coronary Heart Disease Treatment
• Chest Pain Overview
• Coronary Heart Disease Overview
• Coronary Heart Disease Symptoms
• Heart Attack Overview

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